Ben Shen, PhD

Co-chair
Professor
Director, The Natural Products Library Initiative at TSRI
Department of Chemistry
Florida Campus



Scripps Research Joint Appointments

Professor, Department of Molecular Medicine
Professor, Worm Institute for Research and Medicine (WIRM)
Faculty, Graduate Program

Research Focus

Natural Product Biosynthesis, Engineering, and Drug Discovery.  Microorganisms produce a large variety of biologically active substances representing a vast diversity of fascinating molecular architecture not available in any other systems. Our research centers on the chemistry, biochemistry and genetics of the biosynthesis of these secondary metabolites. Blending organic chemistry, biochemistry, and molecular biology, we take a multidisciplinary approach to study the secondary metabolism by asking the following questions: what reactions are available in nature, what are the enzymatic mechanisms of these reactions, how are these reactions linked to produce complex structures, what are the regulatory mechanisms of these pathways, and, ultimately, how can we manipulate nature's biosynthetic machinery for the discovery and development of new drugs. Members of our group gain broad training spanning organic chemistry, biochemistry, microbiology and molecular biology, a qualification that is becoming essential for the modern bioorganic chemists who seek career opportunity in both academia and pharmaceutical and biotechnology industry (http://www.scripps.edu/shen/).

The Natural Products Library Initiative (NPLI) at TSRI.  Natural products are significantly underrepresented in current small molecule libraries.  The current NPL at TSRI consists of: (i) purified natural products with fully assigned structures, (b) MPLC (on C-18 semipreparative column) fractions, and (c) crude extracts.  The NPL is presented in 384-well format with all materials dissolved in DMSO (1 mM for pure compounds and 50 mg/mL for fractions and extracts), compatible with most of the HTS platforms.  The NPL at TSRI currently available for screening includes: (a) 5,500 strains, (b) 500 pure natural products, (c) 4,600 MPLC fractions, and (d) 10,173 crude extracts.  The NPL grows at the rate of 100 strains/month and crude extracts, MPLC fractions, and pure natural products derived thereof.  The NPL provides an unprecedented molecular diversity to screen emerging targets for drug leads, and selected members of the NPL serves as outstanding small molecule probes to interrogate biology (http://www.scripps.edu/shen/NPLI/npliattsri.html).


Education

Ph.D. (Organic Chemistry and Biochemistry), Oregon State University, 1991
M.S. (Chemistry), Chinese Academy of Sciences, 1984
B.S. (Chemistry), Hangzhou University, 1982

Professional Experience

1991-95, Postdoctoral Research Associate, School of Pharmacy, UW-Madison, WI
1995-01, Assistant Professor, Department of Chemistry, University of California, Davis, CA
2001-03, Associate Professor, School of Pharmacy and Department of Chemistry, UW-Madison, WI
2004-10, Professor, School of Pharmacy and Department of Chemistry, UW-Madison, WI
2004-10, Charles M. Johnson Distinguished Chair, School of Pharmacy, UW-Madison, WI
2005-10, Principal Investigator, NCI UW National Cooperative Drug Discovery Group, Madison, WI
2011-16, Professor, Departments of Chemistry and Molecular Therapeutics, TSRI, Jupiter, FL
2014-16, Vice Chair, Department of Chemistry, TSRI, Jupiter, FL
2011-, Director, The Natural Products Library Initiative at TSRI, TSRI, Jupiter, FL
2017-, Professor and Co-Chair, Department of Chemistry, TSRI, Jupiter, FL
2017-, Professor, Department of Molecular Medicine, TSRI, Jupiter, FL2011-2017 Professor (Joint Appointment), Molecular Therapeutics, Scripps Research
2005-2010 Principal Investigator, NCI UW National Cooperative Drug Discovery Group, University of Wisconsin-Madison
2004-2010 School of Pharmacy and Department of Chemistry, University of Wisconsin-Madison
2004-2010 Charles M. Johnson Distinguished Chair, School of Pharmacy, University of Wisconsin-Madison
2001-2003 Associate Professor, School of Pharmacy and Department of Chemistry, University of Wisconsin-Madison
1995-2001 Assistant Professor, Department of Chemistry, University of California, Davis
1991-1995 Postdoctoral Research Associate, University of Wisconsin-Madison

Awards & Professional Activities

1996-01, FIRST Award, NIH
1997-00, Searle Scholar, Searle Scholars Program
1998-03, CAREER Award, NSF
2000, Matt Suffness Award, American Society of Pharmacognosy
2001-06, Independent Scientist Award, NIH
2002, Jack L. Beal Award, American Society of Pharmacognosy
2011, Fellow, American Academy of Microbiology

2011, Fellow, American Association for the Advancement of Science
2015, Promega Biotechnology Research Award, American Society for Microbiology
2018, Charles Thom Award, Society of Industrial Microbiology and Biotechnology

2002-16, Member, Editorial Board of J. Ind. Microbiol. Biotechnol.
2003-17, Member, Editorial Advisory Board of J. Nat. Prod.
2005-17, Member, Advisory Board of Mol. BioSyst.
2006-, Associate Editor, Acta Microbiologica Sinica
2009-, Member, Editorial Board of J. Antibiot.
2011, Guest Co-Editor, J. Antibiot. January issue in memory of C. Richard Hutchinson
2012, Guest Co-Editor, Curr. Opinion Chem. Biol. April issue on Biocatalysis and Biotransformation
2017-, Editor, J. Ind. Microbiol. Biotechnol.


Selected References

All Publications

259. Teijaro, C. N.; Ajeeth Adhikari, A.; Shen, B. (2019) Challenges and opportunities in microbial engineering for natural products. J. Ind. Microbiol. Biotechnol. 46:in press (https://link.springer.com/article/10.1007/s10295-018-2094-5) (SI on Natural Products Discovery and Development).

258. Rudolf, J. D.; Liao-Bin Dong, L.-B.; Zhang, X.; Renata, H.; Shen, B. (2018) Cytochrome P450-catalyzed hydroxylation initiating ether formation in platensimycin biosynthesis. J. Am. Chem. Soc. 140:12349-12353.

257. Yan, X.; Chen, J.-J.; Adhikari, A.; Teijaro, C.; Ge, H.; Crnovcic, I.; Chang, C.-Y.; Annaval, T.; Yang, D.; Rader, C.; Shen, B. (2018) Comparative studies of the biosynthetic gene clusters for anthraquinone-fused enediynes reveal the tailoring steps of tiancimycin biosynthesis. Org. Lett. 20:5918-5921.

256. Annaval, T.; Han, L.; Rudolf, J. D.; Xie, G.; Yang, D.; Chang, C.-Y.; Ma, M.; Crnovcic, I.; Miller, M. D.; Soman, J.; Xu, W.; Phillips, G. N. Jr.; Shen, B. (2018) Biochemical and structural characterization of TtnD, a prenylated FMN-dependent decarboxylase from the tautomycetin biosynthetic pathway. ACS Chem. Biol. 13:2728-2738.

255. Kwong, T.; Ma, M.; Pan, G.; Hindra; Yang, D.; Yang, C.; Lohman, J. R.; Rudolf, J. D.; Cleveland, J. L.; Shen, B. (2018) P450-catalyzed tailoring steps in leinamycin biosynthesis featuring regio- and stereoselective hydroxylations and substrate promiscuities. Biochemistry, 57:5005-5013.

254. Murray, V.; Chen, J. K.; Yang, D.; Shen, B. (2018) The genome-wide DNA sequence specificity of bleomycin analogues in human cells. Bioorg. Med. Chem. 26:4168-4178.

253. Jiang, L.; Pu, H.; Xiang, J.; Su, M.; Yan, X.; Yang, D.; Zhu, X.; Shen, B.; Duan, Y.; Huang, Y. (2018) Huanglongmycin A-C, Cytotoxic Nonaketides from Streptomyces sp. CB09001. Front. Chem. 6:254.

252. McAlpine, J.; et al.; Pauli, G. (2018) The value of universally available raw NMR data for transparency, reproducibility, and integrity in natural product research. Nat. Prod. Rep. 35:in press.

251. Kong, J.; Yi, L.; Xiong, Y.; Huang, Y.; Yang, D.; Yan, X.; Shen, B.; Duan, Y; Zhu, X. (2018) The discovery and development of microbial bleomycin analogues. Appl. Mocribiol. Biotechnol. 102:6791-6798.

250. Dong, L.-B.; Rudolf, J. D.; Deng, M.-R.; Yan, X.; Shen, B. (2018) Discovery of the Tiancilactone Antibiotics by Genome Mining of Atypical Bacterial Type II Diterpene Synthases. ChemBioChem 19:1727-1733

249. Dong, L.-L.; Rudolf, J. D.; Kang, D.; Wang, N.; He, C. Q.; Deng, Y.; Huang, Y.; Houk, K. N.; Duan, Y.; Shen, B. (2018) Biosynthesis of thiocarboxylic acid-containing natural products. Nat. Commun. 9:2362.

248. Chang, C.-Y.; Yan, X.; Crnovcic, I.; Annaval, T.; Chang, C.; Nocek, B.; Rudolf, J. D.; Yang, D.; Hindra; Babnigg, G.; Joachimiak, A.; Phillips, G. N. Jr.; Shen, B. (2018) Resistance to enediyne antitumor antibiotics by sequestration. Cell Chem. Biol. 25:1075-1085.

247. Crnovcic, I.; Gan, F.; Yang, D.; Dong, L.-B.; Schultz, P. G.; Shen, B. (2018) Enzymatic characterization of human bleomycin hydrolase and its effect on engineered bleomycin analogues highlighting its potential use as a protein therapeutic against bleomycin induced pulmonary fibrosis. Bioorg. Med. Chem. Lett. 28:2670-2674 (SIP for Prof. Dale Boger).

246. Wang, N.; Rudolf, J. D.; Dong, L.-B.; Osipiuk, J.; Hatzos-Skintges, C.; Endres, M.; Chang, C.-Y.; Babnigg, G.; Joachimiak, A.; Phillips, G. N. Jr.; Shen, B. (2018) Natural separation of the acyl-CoA ligase reaction results in a non-adenylating enzyme. Nat. Chem. Biol. 14:730-737.

245. Chang, C.-Y.; Lohman, J. R.; Huang, T.; Michalska, K.; Bigelow, L.; Rudolf, J. D.; Jedrzejczak, R.; Yan, X.; Ma, M.; Babnigg, G.; Joachimiak, A.; Phillips, G. N. Jr.; Shen, B. (2018) Structural insights into the free-standing condensation enzyme SgcC5 catalyzing ester bond formation in biosynthesis of the enediyne antitumor antibiotic C-1027. Biochemistry, 57:3278-3288.

244. Deng, Y.; Kang, D.; Shi, J.; Zhou, W.; Sun, A.; Ju, J.; Zhu, X.; Shen, B.; Duan, Y.; Huang, Y. (2018) The semi-synthesis, biological evaluation and docking analysis of the oxime, hydrazine and hydrazide derivatives of platensimycin. MedChemComm, 9:789-794.

243. Chen, J.-J.; Rateb, M. E.; Love, M. S.; Xu, Z.; Yang, D.; Zhu, X.; Huang, Y.; Zhao, L.-X.; Jiang, Y.; Duan, Y.; McNamara, C. W.; Shen, B. (2018) Herbicidins from Streptomyces sp. CB01388 showing anti-cryptosporidium activity. J. Nat. Prod. 81:791-797.

242. Qiu, L.; Tian, K.; Wen Z.; Deng, Y.; Kang, D.; Liang, H.; Zhu, X.; Shen, B.; Duan, Y.; Huang, Y. (2018) Biomimetic stereoselective sulfa-Michael addition leads to potent platensimycin and platencin sulfur analogues against methicillin-resistant Staphylococcus aureus. J. Nat. Prod. 81:316-322.

241. Guo, X.; Crnovcic, I.; Lohman, J. R.; Papinski, M.; Horsman, G. P.; Bechthold, A.; Shen, B. (2018) PokMT1 from the polyketomycin biosynthetic machinery of Streptomyces diastatochromogenes Tü6028 belongs to the emerging family of C-methyltransferases that act on CoA-activated aromatic substrates. Biochemistry 57:1003-1011.

240. Liu, L.; Pan, J.; Wang, Z.; Yan, X.; Yang, D.; Zhu, X.; Shen, B.; Duan, Y.; Huang, Y. (2018) Ribosome engineering and fermentation optimization leads to overproduction of tiancimycin A, a new enediyne natural product from Streptomyces sp. CB03234. J. Ind. Microbiol. Biotechnol. 45:141-151.

239. Yan, X.; Hindra; Ge, H.; Yang, D.; Huang, T.; Crnovcic, I.; Chang, C.-Y.; Fang, S.; Annaval, T.; Zhu, X.; Huang, Y.; Zhao, L.-X.; Jiang, Y.; Duan, Y.; Shen, B. (2018) Discovery of alternative producers of the enediyne antitumor antibiotic C-1027 with high titers. J. Nat. Prod. 81:594-599.

238. Zhu, X.; Kong, J.; Yang, H.; Huang, R.; Huang, Y; Yang, D.; Shen, B.; Duan, Y. (2018) Strain improvement by combined UV mutagenesis and ribosome engineering and subsequent fermentation optimization for enhanced 6′-deoxy-bleomycin Z production. Appl. Microbiol. Biotechnol. 102:1651-1661.

237. Yang, D.; Hindra, Dong, L.-B.; Crnovcic, I.; Shen, B. (2018) Engineered production and evaluation of 6′-deoxy-tallysomycin H-1 revealing new insights into the structure-activity relationship of the anticancer drug bleomycin. J. Antibiot. 71:97-103.

236. Nejad, M. I.; Yang, D.; Shen, B.; Gates, K. S. (2018) Oxidative activation of leinamycin E1 triggers alkylation of guanine residues in double-stranded DNA. Chem. Comm. 54:256-259.

235. Pan, G.; Xu, Z.; Guo, Z.; Hindra; Ma, M.; Yang, D.; Zhou, H.; Gansemans, Y.; Zhu, X.; Huang, Y.; Zhao, L.-X.; Jiang, Y.; Cheng, J.; Van Nieuwerburgh, F.; Suh, J.-W.; Duan, Y.; Shen, B. (2017) Discovery of the leinamycin family of natural products by mining actinobacterial genomes. Proc. Natl. Acad. Sci. USA 114:E11131-E11140.

234. Yan, X.; Chen, J.-J.; Adhikari, A.; Yang, D.; Crnovcic, I.; Wang, N.; Chang, C.-Y.; Rader, C.; Shen, B. (2017) Genome mining of Micromonospora yangpuensis DSM 45577 as a producer of an anthraquinone-fused enediyne. Org. Lett. 19:6192-6195.

233. Annaval, T.; Rudolf, J. D.; Chang, C.-Y.; Lohman, J. R.; Kim, Y.; Bigelow, L.; Jedrzejczak, R.; Babnigg, G.; Joachimiak, A.; Phillips, G. N. Jr.; Shen, B. (2017) Crystal structure of the thioesterase SgcE10 supporting common polyene intermediates in 9- and 10-membered enediyne core biosynthesis. ACS Omega 2:5159-5169.

232. Rudolf, J. D.; Chang, C.-Y.; Ma, M.; Shen, B. (2017) Cytochromes P450 for natural product biosynthesis in Streptomyces: sequence, structure, and function. Nat. Prod. Rep. 34:1141-1172.

231. Zhang, B.; Xu, Z.; Teng, Q.; Pan, G.; Ma, M.; Shen, B. (2017) A Long-range acting dehydratase domain as the missing link for the C17-dehydration in iso-migrastatin biosynthesis. Angew Chem. Int. Ed. 56:7247-7251.

See Shen Laboratory website for complete list of publications (http://www.scripps.edu/shen/researchoverview/publications.html).

See MyBibliography for complete list of publications (

http://www.ncbi.nlm.nih.gov/sites/myncbi/ben.shen.1/bibliography/42110543/public/?sort=date&direction=ascending)

Google Scholar Citations (http://scholar.google.com/citations?hl=en&user=LNnZEd4AAAAJ ).


Links

The Natural Products Library Initiative (NPLI) at TSRI